Figure 3.

Novel transcription factors and pulmonary hypertension. Oct-4, normally associated with embryonic stem cell differentiation, has been suggested to play a role in hypoxia-mediated proliferation of PASMCs through the ability of Hif-2α to bind the Oct-4 promoter and trigger cell growth. Similar to Oct-4, Fhl-1 also was demonstrated to promote PASMC growth and proliferation through activation of the Hif-1/2 factors in response to hypoxia. Increased levels of Notch-3 were shown to induce c-FLIP, an antiapoptotic mediator, in PASMCs, and results in increased apoptosis resistance. Notch-3 also may interact with upstream regulators of the MAPK signaling pathway (including Src and Ras) to promote cell proliferation. Lastly, the Id protein family may act cooperatively to regulate BMP-R-dependent PASMC proliferation via their effects on the cyclin-dependent kinases and have been shown to be affected by prostacyclin therapy, a vital treatment resource for PH patients.